BRAF inhibitor therapy has demonstrated an improvement in survival and has gained FDA approval less than ten years from the first reporting of the BRAFV600E mutation in approximately half of melanomas. This record drug development time attests to the high relevance of this new mode of therapy. However, the initial success is limited by the frequent development of acquired resistance to BRAF inhibitors. In this resubmission we propose an integrated project program grant (PPG) with four projects centered on the understanding of how melanomas become resistant to BRAF inhibitors and how combinatorial strategies can be designed to prevent or treat resistance. We have incorporated the critiques and concerns from the initial review and we provide a markedly improved application with the following projects and cores: Project 1 (Lo) proposes a comprehensive study of acquired resistance pathways as targets for combinatorial treatments using integrated genomic platforms coupled with functional experiments. Project 2 (Graeber) uses mass spectrometry-based phosphoprofiling and protein interaction profiling techniques to characterize the signaling events driving resistance from a systems perspective. Project 3 (Tseng) proposes the use of a microfluidic diagnostics toolbox for quantification of multiple signaling and genomic events, optimized for minimally invasive techniques amenable to repeated sampling, to study the process of acquired resistance to BRAF inhibitors. Project 4 (Ribas) tests the combination of BRAF inhibitor therapy and immunotherapy to prevent resistance to single agent BRAF inhibitors in animal models and in the clinic. The Administrative Core A will provide overall support for the activities of the PPG, including comprehensive biostatistics and bioinformatics support. The Biospecimen and Pathology Core B serves as a repository of in-house generated and oncogenically characterized melanoma cell lines and will process and provide new biopsies from patients treated with BRAF inhibitors. Program integration is achieved through the common (but non-overlapping) scientific goals of addressing resistance to BRAF inhibitors by a group of highly collaborative investigators.